We found that in human prostate carcinoma and in lung carcinoma hexokinase 2 (HK2) expression is markedly elevated, while in normal prostate and lung cells its expression is hardly detectable. HK2 catalyzes the first committed step in glucose metabolism, and is highly expressed in glycolytic cancers. We found that ablation of HK2 in cancer cell lines significantly attenuate their tumorigenicity both in vitro and in vivo. In the first part of this proposal we wil employ mouse models of prostate carcinoma and lung carcinoma, which emulate human prostate and lung carcinomas. We will employ mice in which HK2 can be conditionally deleted in all mouse tissues. These mice will be crossed with mouse strains that develop either prostate carcinoma or lung carcinoma. Following tumor development, HK2 expression will be disrupted to determine whether HK2 deficiency per se can inhibit or reverse tumor progression without adverse physiological consequences. The proposed experiments would overcome a major obstacle that has historically precluded testing the feasibility of these approach, because germ line HK2 deletion is embryonic lethal in mice, but we can now conditionally delete HK2 in all adult tissues using HK2flox/flox mice. In the second part of this proposal, we will delineate the mechanism by which HK2 exerts its effect on tumor cells. We will employ both cancer cells derived from the mouse models and human cancer cells in these studies.